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Cushing’s and Osteoporosis

Editor’s Note: This article uses the term Cushing’s syndrome, which includes all forms of Cushing’s, including Cushing’s Disease.

Cushing’s syndrome has multiple effects on bone metabolism. Elevated cortisol levels directly inhibit bone formation and indirectly influence the skeleton via effects on reproductive hormones, growth hormone, muscle and fat tissue, intestinal calcium absorption, and renal calcium excretion. Certain treatments for Cushing’s syndrome, such as pituitary surgery and/or radiation therapy, may also potentially affect hormonal factors which regulate bone mass. As a result patients with active Cushing’s syndrome frequently have lower measurements of bone mineral density (assessed by dual-energy X-ray absorptiometry [DXA]), abnormalities in bone microarchitecture, lower estimates of bone strength, and an increased risk of fracture compared to healthy individuals. Fractures often occur with minimal or no antecedent injury and can occur in patients with normal measurements of bone mineral density. Maintenance of normal reproductive hormone levels is not adequate to protect against bone loss in patients with Cushing’s syndrome. Bone density loss may be more severe in younger individuals, and childhood growth retardation can occur. Childhood and adolescence is normally a period of rapid bone accrual. Impairment of bone accumulation during this period can therefore affect the attainment of peak bone mass and bone density measurements later in life.

Estimates of the prevalence of osteoporosis (according to bone density measurement by DXA) in active Cushing’s syndrome can approach nearly 50% in some studies. Bone density loss generally appears to be most severe at the spine. Spinal and rib fractures are the most frequently reported sites of bone injury in patients with Cushing’s syndrome. Fortunately, many of these parameters can improve following remission of Cushing’s syndrome, though the extent of improvement may vary. After normalization of cortisol levels, a progressive increase in bone density normally occurs, particularly at the spine and hip. Complete normalization of bone density may occur in some patients, though such gains can require several years or longer. No studies examining changes in bone quality (such as parameters of microarchitecture or modelling of bone strength) after normalization of cortisol levels have yet been published. Data assessing fracture risk after remission of Cushing’s syndrome are very limited. One questionnaire-based study suggested that fracture risk normalizes following remission. In a large case-control study, fracture risk in patients receiving supraphysiologic dosages of glucocorticoids normalized greater than a year after medication discontinuation. That study demonstrated a dose-dependent relationship between glucocorticoids and fracture risk. Prolonged usage of supraphysiologic dosages of medications to replace cortisol after remission of Cushing’s syndrome may hinder the recovery of bone density.

Data examining adjunctive medical therapies for osteoporosis in patients with endogenous Cushing’s syndrome are limited, and management strategies have been partly adapted from experience in patients who are prescribed high dosages of glucocorticoids. Extrapolation of this data has certain limitations since patients treated with glucocorticoids often have an underlying disease which may independently affect bone metabolism and also may lack some of the comorbidities that can accompany endogenous Cushing’s syndrome. There are no guidelines that specifically address the treatment of osteoporosis in endogenous Cushing’s syndrome. Guidelines for the treatment of osteoporosis associated with prescription glucocorticoids utilize fracture risk calculations that have not been validated for endogenous Cushing’s syndrome and also stratify patients according to glucocorticoid dosage. The identification of patients with Cushing’s syndrome who are appropriate candidates for additional treatment with anti-osteoporotic agents, the choice of therapy, and optimal timing for intervention require additional study.

Author:Dr. Alexander Faje, Spring, 2016
Editor’s Note: Alexander Faje, MD is an endocrinologist in the Neuroendocrine Clinical Center and a faculty member in the Neuroendocrine Unit at the Massachusetts General Hospital, and an Instructor of Medicine at Harvard Medical School. He is a clinical researcher and clinician, with a focus on pituitary disease.

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